ABSTRACT – EXPERIMENTAL THERAPEUTICS (ET) PROGRAM Overview and Goals: The ET Program is the major translational/clinical research engine of the O'Neal with the goals of identifying novel targets and developing new imaging techniques that can inform innovative therapeutic strategies and provide cancer patients with an enhanced opportunity for improved survival, increased freedom from disease progression, and improved quality of life. Research Highlights: Discovery of new pre-clinical targets such as LIMK2 and PAK4, their in vivo validation in pre-clinical models and medicinal chemistry efforts to develop clinical grade inhibitors to these targets will provide novel therapeutic opportunities for triple-negative breast cancer (TNBC) and bladder cancer patients, with direct implications for other cancer types in our catchment area. Advances in imaging markers of patient response to immunotherapies, including hypoxia and granzyme B, have led to clinical trials in breast cancer, melanoma, and non-small cell lung cancer, all of which are of importance in our catchment area. Successful inter- and intra-programmatic collaborative bench to bedside efforts continue to result in clinical translation, including novel combinations with EGFR and PARP inhibition in TNBC or EGFR and DNA repair checkpoint inhibition in head and neck cancer. Program Activities: ET co-leaders work closely with O'Neal leadership to enable intra- and inter-programmatic collaborations through program activities enhanced by SPORE (Cervical cancer; P50 CA098252) and P01 funding (Cancer Prevention; P01 CA210946), significant collaborations with Southern Research through the Alabama Drug Discovery Alliance, and partnerships with industry. Strong collaborations with national consortia have continued, including the NCI NCTN Lead Academic Partnership Site grant (UG1 CA233330) and the Translational Breast Cancer Research Consortium. Members: The program has 60 members from 14 departments and 3 schools. NCI funding is $3.6M, cancer-relevant, peer-reviewed funding is $7.8M, and total cancer-relevant funding is $23M. 2,065 patients were enrolled in therapeutic trials over the current CCSG cycle, including 12% to investigator-initiated trials, 31% to pilot/Phase I studies, 10% to Phase I/II trials, and 37% to Phase III trials. The program had 1,123 publications over the current CCSG cycle including 34% inter-programmatic, 24% intra-programmatic, 68% resulting from collaborations with other institutions, and 13% in journals with an impact factor of 9 or greater. Future Directions: We plan to enhance current strengths in O'Neal cross-cutting research themes as laid out in the strategic plan, namely obesity and metabolism in cancer, cancer immunology, imaging, target identification and therapeutic development. We will work with the office of Community Outreach and Engagement to leverage recent support e.g., Bridge the Transdisciplinary Cancer Research Continuum supplement (P30 CA013148-48S6), CATCH-U...